CD74 regulates the tumor immunosuppressive microenvironment in triple-negative brest cancer

CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD), which regulates transcription in naive B and chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the role of CD74 in the regulation of the immunosuppressive tumor microenvironment (TME) in triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype, in which there is a massive infiltration of immune cells to the tumor microenvironment, making this tumor a good candidate for immunotherapy. The tumor and immune cells in TNBC express high levels of CD74, however, the function of this receptor in this environment was not fully characterized. Regulatory B cells (Bregs) and tolerogenic dendritic cells )tol-DCs( were previously shown to attenuate the antitumor immune response in TNBC. Here, we demonstrate that CD74 enhances tumor growth by inducing the expansion of tumor-infiltrating tol-DCs and Bregs. Utilizing CD74-KO mice, conditionally CD74 -/- Cre-flox mice lacking CD74 in CD23+ mature B cells and mice lacking CD74 in the CD11c+ population and a CD74 inhibitor (DRQ), revealed that MIF secreted from the tumor cells activate CD74 expressed on DCs. This activation induces the binding of CD74-ICD to the SP1 promotor, resulting in the upregulation of SP1 expression. SP1 binds the IL-1β promotor, leading to the downregulation of its transcription. The reduced levels of IL-1β lead to decreased anti-tumor activity by allowing expansion of the tol-DC, which induce the expansion of the Breg population, suggesting the cross-talk between these two populations. Taken together, these results suggest that CD74+ CD11c+ DCs are the dominant cell type involved in the regulation of the TNBC progression. These findings indicate that CD74 might serve as a novel therapeutic target in triple-negative breast cancer.